Preparation method of imrecoxib intermediate

Abstract

According to the preparation method of the imrecoxib intermediate, DMTMM serves as a condensing agent, TEMPO / sodium hypochlorite serves as an oxidizing agent, the production cost is saved, meanwhile, the safety risk possibly introduced in the medicine production process is greatly reduced, and compared with the prior art, the preparation method of the imrecoxib intermediate provided by the invention is simpler to operate, safer, high in yield and suitable for industrial production. And the product has higher purity and is more suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of an intermediate of Imrecoxib. Background Art

[0002] Imrecoxib is a highly selective COX-2 inhibitor developed by Jiangsu Hengrui Medicine Co., Ltd., and is used to treat and relieve the pain symptoms of osteoarthritis and postoperative inflammation. The chemical name of Imrecoxib is: (N-n-propyl-3-(4-methylphenyl)-4-(4-methylsulfonylphenyl)-2,5-dihydropyrrole-2-one), and the structure is shown in formula (I):

[0003]

[0004] CN1134413C discloses a preparation method of Imrecoxib. Using 4-methylsulfonyloxystyrene as the raw material, Imrecoxib is prepared through nucleophilic ring-opening with n-propylamine, amidation with p-methylphenylacetyl chloride, hydroxyl oxidation and condensation cyclization reactions. The synthetic route is as follows:

[0005]

[0006] In the above route, p-methylphenylacetyl chloride is used in the amidation step. The acyl chloride will not only react with the amino group in intermediate (IV), but also react with the hydroxyl group, generating esterification impurities, increasing the purification difficulty, and thus affecting the yield. Patent CN107586268A optimizes and modifies on the basis of the above route, replaces p-methylphenylacetyl chloride with p-methylphenylacetic acid, and prepares amide intermediate (II) under the promotion of condensing agents such as CDI and EDCI, improving the reaction yield and product purity of this step. However, condensing agents such as CDI and EDCI are sensitive to moisture in the reaction system, and lower moisture needs to be controlled for industrial scale-up, increasing the production difficulty.

[0007] Patents CN1134413C and CN107586268A use oxidants such as Jones reagent or chromium anhydride pyridine in the oxidation step. The oxidation reaction system of chromium-containing oxidants is relatively viscous, with high cost, low yield, and difficult product separation, which is not conducive to industrial scale-up. Moreover, the residue of heavy metal chromium will affect the product quality of the API. The chromium-containing wastewater is difficult to treat, with a large potential for environmental pollution, and at the same time, there are greater risks to the safety and health of personnel during the production process. Summary of the Invention

[0008] The content of the present invention is to overcome the deficiencies of the prior art. The technical problem to be solved by the present invention is to provide a preparation method of an intermediate N-propyl-N-[2-oxo-2-(4'-methylsulfonylphenyl)]ethyl-4-methylphenylacetamide (II). This method uses DMTMM, which does not require water avoidance, as a condensing agent, and the intermediate IV and 4-methylphenylacetic acid can react simply and quickly to obtain an intermediate (III) with high yield and purity; subsequently, TEMPO / 5%-10% sodium hypochlorite is used as an oxidant to efficiently oxidize the intermediate (III) to the intermediate II.

[0009] To solve the above problems, the technical solution provided by the present invention is as follows:

[0010] A preparation method of an intermediate of loxoprofen sodium, wherein the intermediate is N-propyl-N-[2-oxo-2-(4'-methylsulfonylphenyl)]ethyl-4-methylphenylacetamide (Formula II), and is characterized in that the preparation method of the intermediate comprises the following steps:

[0011] Step (1): Add the compound (IV), 4-methylphenylacetic acid and a condensing agent to a reaction solvent, stir and react at a certain temperature, and perform post-treatment after the reaction is complete to obtain an oily intermediate (III). The reaction formula is as follows:

[0012]

[0013] The condensing agent is DMTMM;

[0014] Step (2): Add the intermediate (III), TEMPO and a catalyst to a reaction solvent, slowly dropwise add a 5%-10% aqueous sodium hypochlorite solution under an ice-water bath, and react until no raw materials remain to obtain the compound (Formula II). The reaction formula is as follows:

[0015]

[0016] The catalyst is sodium bromide or potassium bromide.

[0017] Further, the amount of the condensing agent DMTMM used in step (1) is in a molar ratio of intermediate (IV): DMTMM of 1:1.00 - 1.20 equivalents, preferably 1.05 equivalents;

[0018] Further, the selected solvent in step (1) includes one or more of N,N-dimethylformamide, N-methylpyrrolidone, toluene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, and water, preferably toluene; the amount of the solvent used is 3 - 50 times the mass of the intermediate (IV).

[0019] Further, the reaction temperature in step (1) is 0 - 50°C, preferably 10 - 40°C.

[0020] Further, the selected solvent in step (2) includes one or more of dichloromethane and toluene, preferably toluene; the amount of the solvent is 2 to 35 times the mass of intermediate (III); in the continuous feeding step, the amount of the solvent is 3 to 50 times the mass of intermediate (IV).

[0021] Further, the weight ratio of TEMPO / 5%-10% sodium hypochlorite solution used in step (2) is 1:100 to 1:85, and the amount of sodium hypochlorite used is 2.5 to 3.5 times the mass of intermediate (III); in the continuous feeding operation, the amount of sodium hypochlorite used is 3.75 to 5.25 times the mass of intermediate (IV).

[0022] Further, the catalyst used in step (2) is potassium bromide or sodium bromide, and the usage amount is 3 to 10% of the weight of formula (III). In the continuous feeding operation, the usage amount of the catalyst is 4.5 to 15.0% of the weight of intermediate (IV). Further, the reaction temperature in step (2) is 0 to 50 °C, preferably 10 to 40 °C.

[0023] The intermediate (III) prepared by the present invention has mild reaction conditions, high purity of the intermediate (III), and the content of esterification impurity (VI) is less than 0.10%. The structural formula of the esterification impurity is as follows:

[0024]

[0025] The present invention further studies that based on the relatively high yield and purity of the preparation of intermediate (III) by the condensation reaction, the two-step reactions of condensation and oxidation can be continuously operated to prepare intermediate (II), further optimizing the process. Specifically: 4-methylphenylacetic acid, compound (IV) and a condensing agent are added to a reaction solvent, and stirred and reacted at a certain temperature. After the condensation reaction is complete, an aqueous sodium bicarbonate solution is added, separated, water is added to the organic layer, a catalyst and TEMPO are added, and a 5%-10% sodium hypochlorite solution is slowly added dropwise under an ice-water bath. After the reaction is completed, it is treated to obtain compound (formula II); the condensing agent is DMTMM, and the catalyst is sodium bromide or potassium bromide:

[0026]

[0027] The beneficial effects of the present invention are as follows: Using DMTMM as a condensing agent, the reaction operation is simple, and the condensing agent will not react with the alcohol group in the intermediate (IV) of etoricoxib to produce a large amount of esters; Using TEMPO / 5%-10% sodium hypochlorite as an oxidant, the oxidation reaction is green, mild, low-cost, easy to post-treat, and no heavy metals are introduced. While saving production costs, it also greatly reduces the potential safety risks that may be introduced during the production of drugs. Compared with the prior art, the preparation method of the intermediate (II) provided by the present invention is simpler, safer, has a higher yield, and the product has a higher purity, and is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is the HPLC chromatogram of the compound (III) prepared in Experiment 5) of Example 1;

[0029] Figure 2 It is the HPLC chromatogram of the compound (II) prepared in Experiment 2) of Example 2;

[0030] Figure 3 It is the HPLC chromatogram of etoricoxib prepared in Experiment 2) of Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0031] The following examples illustrate the present invention, but do not limit the present invention. In the art, simple substitutions or improvements made by those skilled in the art to the present invention fall within the scope of the technical solutions protected by the present invention.

[0032] Comparative Example:

[0033] 1) Preparation of compound (III) using thionyl chloride

[0034] 4-Methylphenylacetic acid (0.6 g, 4.0 mmol) and thionyl chloride (4 ml) were heated to reflux for 1.5 h, the thionyl chloride was distilled off, and tetrahydrofuran (5 ml) was added to obtain a tetrahydrofuran solution of 4-methylphenylacetyl chloride.

[0035] Compound (IV) (1.0 g, 3.9 mmol) was dissolved in tetrahydrofuran (4 ml) and pyridine (1.6 ml). The above-mentioned tetrahydrofuran solution of 4-methylphenylacetyl chloride was slowly added dropwise under an ice-water bath. After the addition was completed, the reaction was continued for 1 hour. After the solvent was distilled off under reduced pressure, dichloromethane (10 ml) was added. The organic layer was washed with 10 ml of 1N hydrochloric acid, saturated sodium carbonate solution and water respectively, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.8 g of an oily compound (III), with a yield of 70% and a purity of 84.2%, and the esterification impurity was 13.2%.

[0036] 2) Preparation of compound (III) using CDI / DCC / DIC / EDCI

[0037] 4-Methylphenylacetic acid (0.6 g, 4.0 mmol) was added to anhydrous tetrahydrofuran (10 ml), and CDI (0.7 g, 4.4 mmol) was added. After reacting at 50 °C for 1 hour, compound (IV) (1.0 g, 3.9 mmol) was added and the reaction was continued for 1 hour. The solvent was removed under reduced pressure. Dichloromethane (10 ml) was added, and the organic layer was washed with 10 ml each of 1N hydrochloric acid, saturated sodium carbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 1.4 g of an oily compound (III) with a yield of 95% and a purity of 98.2%, and the esterification impurity was 1.1%.

[0038] Using the same material ratio and post-treatment operation as above, the condensing agents were selected from DCC, DIC, and EDCI. When DCC was used as the condensing agent, 0.1 equivalent of DMAP relative to the amount of 4-methylphenylacetic acid was added as a catalyst; when EDCI was used as the condensing agent, 0.1 equivalent of HOBT relative to the amount of 4-methylphenylacetic acid was added as a catalyst. The results are summarized in the following table:

[0039]

[0040]

[0041] 3) Compound (II) was prepared by oxidizing compound (III) with Jones reagent

[0042] Prepare Jones reagent: 4.4 g of CrO 3 was added to 7.2 g of water and stirred until dissolved, and 8.3 g of concentrated sulfuric acid was slowly added dropwise in an ice-water bath.

[0043] Compound (III) (10.0 g, 25.6 mmol) was added to acetone (150 ml) and dissolved. The above-prepared Jones reagent was slowly added dropwise in an ice-water bath. After reacting for 1 hour, isopropanol (30 ml) was added and the reaction was continued for 2 hours. The solvent was removed by concentration under reduced pressure. Water (100 ml) was added to the concentrated residue, and the mixture was extracted twice with dichloromethane (100 ml). The organic layers were combined, washed with 100 ml each of saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 6.8 g of a solid compound (II) with a yield of 68% and a purity of 94.7%.

[0044] Example 1: Preparation of compound (III)

[0045] 1) Prepared using DMTMM, with DMF as the solvent

[0046] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol), compound (IV) (10.0 g, 39.0 mmol) were added to N,N-dimethylformamide (100 ml), then DMTMM (11.3 g, 41.0 mmol) was added. The reaction was carried out at 20 - 30 °C for 1 hour until complete. Dichloromethane (100 ml) and 5% sodium bicarbonate (100 ml) were added to the reaction solution. After separating the organic layer, the organic layer was washed with water (100 ml) twice. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 14.8 g of an oily compound (III) with a yield of 97.8%, a purity of 98.9%, a content of 97.7%, and an esterification impurity content of 0.08%. [M+H] + : 390.5, C 21 H 27 O 4 NS。

[0047] 2) Prepared using DMTMM, with methanol as the solvent

[0048] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol), compound (IV) (10.0 g, 39.0 mmol) were added to methanol (100 ml), then DMTMM (11.3 g, 41.0 mmol) was added. The reaction was carried out at 20 - 30 °C for 1 hour until complete. The solvent was removed under reduced pressure, dichloromethane (100 ml) and 5% sodium bicarbonate (100 ml) were added. After separating the organic layer, the organic layer was washed with water (100 ml) twice. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 13.0 g of an oily compound (III) with a yield of 85.9%, a purity of 98.6%, a content of 98.3%, and an esterification impurity content of 0.07%.

[0049] 3) Prepared using DMTMM, with dichloromethane as the solvent

[0050] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol), compound (IV) (10.0 g, 39.0 mmol) were added to dichloromethane (100 ml), then DMTMM (11.3 g, 41.0 mmol) was added. The reaction was carried out at 20 - 30 °C for 1 hour until complete. 5% sodium bicarbonate (100 ml) was added to the reaction solution. After separating the organic layer, the organic layer was washed with water (100 ml) twice. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 14.9 g of an oily compound (III) with a yield of 98.4%, a purity of 99.7%, a content of 98.5%, and an esterification impurity content of 0.04%.

[0051] 4) Prepared using DMTMM, with water as the solvent

[0052] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol), compound (IV) (10.0 g, 39.0 mmol) were added to water (100 ml), then DMTMM (11.3 g, 41.0 mmol) was added. The reaction was carried out at 20 - 30 °C for 1 hour until complete. Dichloromethane (100 ml) and 5% sodium bicarbonate (100 ml) were added to the reaction solution. After separating the organic layer, the organic layer was washed twice with water (100 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 14.6 g of an oily compound (III), with a yield of 96.5%, a purity of 96.8%, a content of 96.8%, and an esterification impurity content of 0.09%.

[0053] 5) Prepared using DMTMM, with toluene as the solvent

[0054] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol), compound (IV) (10.0 g, 39.0 mmol) were added to toluene (100 ml), then DMTMM (11.3 g, 41.0 mmol) was added. The reaction was carried out at 20 - 30 °C for 1 hour until complete. 5% sodium bicarbonate (100 ml) was added to the reaction solution. After separating the organic layer, the organic layer was washed twice with water (100 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 15.1 g of an oily compound (III), with a yield of 99.8%, a purity (RT: 20.35 min) of 99.8%, a content of 98.9%, and an esterification impurity (RT: 22.43 min) content of 0.07%.

[0055] Example 2: Preparation of compound (II)

[0056] 1) TEMPO oxidation, with dichloromethane as the solvent

[0057] Compound (III) (10.0 g, 25.6 mmol), TEMPO (0.3 g, 3% based on the weight of compound III), potassium bromide (0.3 g, 3% based on the weight of compound III) were added to dichloromethane (100 ml) and water (20 ml). A 10% sodium hypochlorite solution (28.6 g, 38.4 mmol) was slowly added dropwise under an ice - water bath. After the addition was complete, the reaction continued for 5 hours until complete. Sodium sulfite solution (100 ml) was added to the reaction solution. The aqueous layer was separated, and the organic layer was further washed with sodium sulfite solution (100 ml) and water (100 ml), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 10.0 g of a solid compound (II) (RT: 18.91 min, consistent with the RT obtained in the comparative example), with a yield of 100% and a purity of 98.7%.

[0058] 1 H NMR(600MHz,CDCl3 ) δ 8.12 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.15 (q, J = 8.1 Hz, 4H), 4.72 (s, 2H), 3.77 (s, 2H), 3.44 - 3.29 (m, 2H), 3.07 (s, 3H), 2.33 (s, 3H), 1.63 - 1.46 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). [M + H] + : 388.0. C 21 H 25 O 4 NS.

[0059] 2) TEMPO oxidation, using toluene as the solvent

[0060] Compound (III) (10.0 g, 25.6 mmol), TEMPO (0.3 g, 3% based on the weight of compound III), potassium bromide (0.3 g, 3% based on the weight of compound III) were added to toluene (100 ml) and water (20 ml). A 10% sodium hypochlorite solution (28.6 g, 38.4 mmol) was slowly added dropwise under an ice - water bath. After the addition was complete, the reaction continued for 5 hours until the reaction was complete. The reaction mixture was added to a sodium sulfite solution (100 ml), filtered, and dried to obtain 9.5 g of solid compound (II) with a yield of 95.5% and a purity of 99.7%.

[0061] Example 3: Continuous feeding preparation of compound (II)

[0062] 1) Continuous feeding using dichloromethane as the solvent

[0063] 4 - Methylphenylacetic acid (6.0 g, 40.0 mmol) and compound (IV) (10.0 g, 39.0 mmol) were added to dichloromethane (150 ml). Subsequently, DMTMM (11.3 g, 41.0 mmol) was added, and the reaction was carried out at 20 - 30 °C for 1 hour until the reaction was complete. 5% sodium bicarbonate (100 ml) was added to the reaction mixture. After separating the organic layer, the organic layer was washed twice with water (100 ml). Water (30 ml), potassium bromide (0.45 g), and TEMPO (0.45 g) were added to the organic layer. A 10% sodium hypochlorite solution (44.6 g, 60.0 mmol) was slowly added dropwise under an ice - water bath. After the addition was complete, the reaction continued for 5 hours until the reaction was complete. The reaction mixture was added to a sodium sulfite solution (150 ml), the aqueous layer was separated, and the organic layer was further washed with a sodium sulfite solution (150 ml) and water (150 ml), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 15.0 g of solid compound (II) with a yield of 99.6% and a purity of 97.8%.

[0064] 2) Continuous feeding using toluene as the solvent

[0065] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol), compound (IV) (10.0 g, 39.0 mmol) were added to toluene (60 ml), and then DMTMM (11.3 g, 41.0 mmol) was added. The reaction was carried out at 20 - 30 °C for 1 hour until complete. 5% sodium bicarbonate (100 ml) was added to the reaction solution. After separating the organic layer, the organic layer was washed with water (100 ml) twice. Water (30 ml), potassium bromide (0.45 g), and TEMPO (0.45 g) were added to the organic layer. A 10% sodium hypochlorite solution (44.6 g, 60.0 mmol) was slowly added dropwise under an ice - water bath. After the addition was completed, the reaction continued for 5 hours until complete. Sodium sulfite solution (150 ml) was added to the reaction solution, and 14.3 g of solid compound (II) was obtained by filtration, with a yield of 95.0% and a purity of 99.2%.

[0066] Example 4: Kilogram - scale preparation of etoricoxib

[0067] 1) Preparation of compound (II)

[0068] 4 - Methylphenylacetic acid (2.1 kg, 14.0 mol), compound (IV) (3.5 kg, 13.6 mol) were added to toluene (20 L), and then DMTMM (3.9 kg, 14.0 mol) was added. The reaction was carried out at 20 - 30 °C for 1 hour until complete. 5% sodium bicarbonate (20 L) was added to the reaction solution. After separating the organic layer, the organic layer was washed with water (20 L) twice. Water (10 L), potassium bromide (0.2 kg), and TEMPO (0.2 kg) were added to the organic layer. A 10% sodium hypochlorite solution (17.8 kg, 23.9 mol) was slowly added dropwise under an ice - water bath. After the addition was completed, the reaction continued for 5 hours until complete. Sodium sulfite solution was added to the reaction solution, and 5.02 kg of solid compound (II) was obtained by filtration, with a yield of 95.3% and a purity of 99.1%.

[0069] 2) Preparation of etoricoxib

[0070] Compound (II) (5.0 kg, 12.9 mol), potassium carbonate (3.6 kg, 25.8 mol) were added to ethanol (100 L) and water (100 L). The mixture was heated to reflux. After 2 hours, the reaction was complete. After cooling, ice - water (100 L) was added. The pH was adjusted to 6.5 - 7.0 with 1N hydrochloric acid in an ice - water bath. The solid obtained by filtration was added to ethanol (100 L), and neutral activated carbon (0.5 kg) was added. The mixture was heated to 70 °C for decolorization, followed by hot filtration, crystallization, filtration, and drying to obtain 3.81 kg of white solid, with a yield of 80.0% and a purity of 99.9%.

[0071] 1 H NMR(600MHz,CDCl3 ) δ 7.85 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 3.0 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 4.30 (s, 2H), 3.56 (t, J = 7.4 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H), 1.71 (dd, J = 14.7, 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[0072] The English abbreviations used in the specification and claims have the following meanings.

[0073] Abbreviation Full name CDI N,N’-Carbonyldiimidazole <![CDATA[CrO 3 > Chromium trioxide DMTMM 4-(4,6-Dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride TEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl DMF N,N-Dimethylformamide

[0074] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the inventive concept of the present invention, several modifications and improvements can be made, and these all belong to the protection scope of the present invention.

Claims

1. A method for preparing an erlotinib intermediate, characterized in that: The intermediate is N-n-propyl-N-[2-oxo-2-(4'-methylsulfonylphenyl)]ethyl-4-methylphenylacetamide (Formula II), and the preparation method of the intermediate comprises the following steps: Step (1): Add compound (IV), 4-methylphenylacetic acid and a condensing agent into a reaction solvent, stir and react at a certain temperature, and after the reaction is complete, perform post-treatment to obtain an oily intermediate (III). The reaction formula is as follows: The condensing agent is DMTMM; Step (2): Add the intermediate (III), TEMPO and the catalyst to the reaction solvent, slowly dropwise add 5%-10% sodium hypochlorite aqueous solution under an ice-water bath, react until no raw material remains, and post-treat to obtain a compound (Formula II), the reaction formula is as follows: The catalyst is sodium bromide or potassium bromide.

2. A method for preparing an erlotinib intermediate, characterized in that: The intermediate is N-n-propyl-N-[2-oxo-2-(4'-methylsulfonylphenyl)]ethyl-4-methylphenylacetamide (Formula II), and the preparation method of the intermediate comprises the following steps: 4-Methylphenylacetic acid, compound (IV) and a condensing agent are added to a reaction solvent, stirred at a certain temperature for reaction, and after the reaction is complete, a sodium bicarbonate aqueous solution is added, and water, a catalyst and TEMPO are added to the organic layer after separation, and a 5%-10% sodium hypochlorite solution is slowly added dropwise under an ice-water bath, and after the reaction is complete, a compound (Formula II) is obtained by treatment; the condensing agent is DMTMM, and the catalyst is sodium bromide or potassium bromide; 3. The preparation method according to claim 1, characterized in that: The post-treatment of step (1) comprises adding a sodium bicarbonate aqueous solution after the reaction is complete, separating the liquids, washing, drying and concentrating to obtain an oily intermediate (III).

4. The preparation method according to claim 1, characterized in that: The reaction solvent of step (1) is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, toluene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol and water; the reaction solvent of step (2) is selected from dichloromethane and toluene.

5. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of compound (IV), 4-methylphenylacetic acid and condensing agent is 1:1.00-1.20:1.00-1.

20.

6. The preparation method according to claim 1, characterized in that: The reaction temperature of step (1) is 0-50°C; the reaction temperature of step (2) is 0-50°C.

7. The preparation method according to claim 1, characterized in that: The weight ratio of TEMPO / 5%-10% sodium hypochlorite solution is 1:100 to 1:85, and the sum of the mass of TEMPO and 5%-10% sodium hypochlorite solution is 2.5 to 3.5 times the mass of the intermediate (III).

8. The preparation method according to claim 1, characterized in that: The amount of the catalyst used is 3-10% by weight of the intermediate (III).

9. The preparation method according to claim 2, characterized in that: The reaction temperature is 0-50° C., the weight ratio of TEMPO / 5%-10% sodium hypochlorite solution is 1:100-1:85, the sum of the mass of TEMPO and 5%-10% sodium hypochlorite solution is 3.75-5.25 times the mass of the intermediate (IV), and the amount of the catalyst used is 4.5-15.0% of the weight of the intermediate (IV).

10. The preparation method according to claim 2, characterized in that: The molar ratio of the compound (IV), 4-methylphenylacetic acid and the condensing agent is 1:1.00-1.20:1.00-1.20; the reaction solvent is selected from toluene and dichloromethane.

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